Influence of secobarbital and chlorpromazine on precentral neuron activity during attentive behavior in monkeys

Precentral motor cortex neurons were studied under non-drug and drug conditions in three trained monkeys during the performance of a go-no go visual attention task. The two drugs studied, secobarbital and chlorpromazine, produced differing patterns of effect on components of the motor sequence involved in reaction time. The following components were considered: The SF interval or the period from stimulus onset to change in neuronal firing; the FR interval, which is the period from change in firing to the beginning of the task response; and MT or movement time, which is the time necessary to complete the response. Secobarbital produced an increase of 80% in SF and a relatively small average change in FR although there was considerable variability in the latter. MT was decreased in most secobarbital experiments. Anatomical factors relating to the FR variability were considered, and the MT decrease was discussed in terms of possible excitatory effects of the drug.Chlorpromazine produced small increases in SF, FR and MT, alternating with periods of complete abolition of performance. The results were discussed in terms of theories of attention deficit following administration of secobarbital and chlorpromazine.Part of the costs of this work were supported by Grants MH-12568 (N.I.M.H.) and DA-00257 (N.I.D.A.) from the United States Public Health Service. Some of these results were presented at the 1974 Meeting of the Federation of Societies for Experimental Biology and were published as an abstract by Otero and Mirsky (1974) in the proceedings of that meeting.Supported by a John E. Fogarty International Center, N.I.H. P.H.S. Fellowship No. 5-F05-TWO-1668-01/02, and by Grant Foundation Award, F.A.E.S., N.I.M.H.Supported by Research Scientist Award PHS 5 K05 MH14915-08 from N.I.M.H.     

The effects of chlorpromazine and secobarbital on matching from sample and discrimination tasks in monkeys

Summary Monkeys were trained in the performance of a matching from sample task and in two simultaneous visual discrimination tasks differing in level of difficulty. In the case of the matching task, four doses each of chlorpromazine and of secobarbital were administered to the animals according to a balanced design. The procedure was then replicated. The results of the matching task indicated that chlorpromazine produced many errors of omission and few errors of commission. The latter kind of error as well as other measures of confused responding were seen primarily with secobarbital. In the case of the visual discriminations, secobarbital produced greater impairment of the more difficult (pattern) task than of the simpler (color) task; chlorpromazine had equivalent effects on the two tasks. The similarity between the secobarbital action and the behavioral consequences of certain cortical lesions in the monkey was discussed.This work was supported by the following grants from the National Institute of Mental Health, Public Health Service: Research Grant MH-12568; Special Fellowship 1-F3-25,128 (Dr. Bakay Pragay); Research Scientist Award 5-KO-5MH-14,915 (Dr. Mirsky); Predoctoral Fellowship 1-F2-NB-32-103 (Dr. Abplanalp).     

EEG correlates of impaired attention performance under secobarbital and chlorpromazine in the monkey

The effects of secobarbital and chlorpromazineupon behavior in a continuous, rapidly presented successive (go-no go) discrimination (attention) task were evaluated in six Macaca mulatta monkeys. Simultaneous monitoring of EEG activity from epidural and subcortical electrodes permitted an evaluation of the nature of altered central nervous system events during erroneous performance (errors of omission) on this task. The computer-assisted analysis of pre-stimulus and post-stimulus EEG frequency activity (baseline crossings) suggests that the best measure of attentive behavior from the pre-stimulus EEG is percentage of beta 2 (25–40 cps) activity. No difference could be observed between drugs or among cerebral placements in this regard. This was determined by comparing measures of EEG frequency, pooled for a given test period, with performance from the same test period. On a trial-by-trial basis, however, the beta 2 measure in the pre-stimulus epoch failed to distinguish correct responses from errors of omission.Separation between correct responses and errors of omission is possible if comparisons are made between the changes in percentage of beta 2 activity in the pre-stimulus vs. post-stimulus epochs. For both drugs, the largest absolute change in beta 2 pre- vs. post-stimulus occurs with correct positive trials and the smallest change with correct negative trials. For secobarbital, no difference could be detected between correct and incorrect positive trials. For chlorpromazine, however, there was significantly less change in beta 2 for incorrect positive than for correct positive trials. The results were interpreted in terms of the hypothesis that secobarbital produces errors by depression of the general level of activation whereas chlorpromazine acts by reducing the sensory input which is necessary for correct discrimination performance.Some of these results were presented to the IXth Meeting of the Collegium Internationale Neuropsychopharmacologicum, Paris, France, July, 1974. Supported by USPHS grant No. MH 12568 from the National Institute of Mental Health. The authors are grateful to Dr. Eva Bakay Pragay for her wise counsel.Research Scientist Awardee K05 14915 of the National Institute of Mental Health.     

Human social conversation: Effects of ethanol,secobarbital and chlorpromazine

Effects of oral ethanol, secobarbital and chlorpromazine on human vocalization were studied in a dyadic social situation using repeated observations within subject pairs. Throat microphones and voice operated relays were used to measure quantitative aspects of vocalization (conversational speech) during daily experimental sessions. Ethanol (1–6 oz of 95-proof) and secobarbital (30–300 mg) produced dose-related increases in vocalization by the subject who received active drug, while vocalization by the partner who received placebo only was not generally altered systematically. Chlorpromazine (25–100 mg) produced dose-related decreases in amount of vocalization by the subject and vocalization by partners tended to decrease as well on days when the subject received active drug. Selected scales from the Addiction Research Center Inventory were administered following social sessions to assess subjective drug effects. No consistent changes on ARCI scales were obtained after ethanol or secobarbital, while chlorpromazine produced dose-related increases on the PCAG scale. Overall, quantitative measures of vocalization in a social context provided a reliable and sensitive indicator of dose-related drug effects.     

Effects of phencyclidine,secobarbital and diazepam on eye tracking in rhesus monkeys

Rhesus monkeys were trained to track a moving disk using a procedure in which responses on a lever were reinforced with water delivery only when the disk, oscillating in a horizontal plane on a screen at a frequency of 0.4 Hz in a visual angle of 20 degrees, dimmed for a brief period. Pursuit eye movements were recorded by electrooculography (EOG). IM phencyclidine, secobarbital, and diazepam injections decreased the number of reinforced lever presses in a dose-related manner. Both secobarbital and diazepam produced episodic jerky-pursuit eye movements, while phencyclidine had no consistent effects on eye movements. Lever pressing was disrupted at doses which had little effect on the quality of smooth-pursuit eye movements in some monkeys. This separation was particularly pronounced with diazepam. The similarities of the drug effects on smooth-pursuit eye movements between the present study and human studies indicate that the present method using rhesus monkeys may be useful for predicting drug effects on eye tracking and oculomotor function in humans.     

不同时间睡眠剥夺对健康男性注意力的影响及莫达非尼的干预作用

目的：观察不同时间睡眠剥夺对健康青年男性注意力的影响以及新型中枢兴奋剂莫达非尼的干预作用。方法：采用自身交叉设计,10名健康青年男性先后进行3次睡眠剥夺,第1次不服药（剥夺组）,后2次睡眠剥夺中被试者交叉服用莫达非尼和安慰剂,其中服用莫达非尼的被试者归入莫达非尼组,服用安慰剂的被试者归入安慰剂组。药物在1次睡眠剥夺中分先后2次服用（分别于睡眠剥夺14h和27h服用）,每次服药后3h进行持续性注意力任务（CPT）、选择性注意力（Stroop试验）测试,剥夺组也在同样时间点进行测试,即每次睡眠剥夺进行2次测试,分别称第Ⅰ、Ⅱ次测试。结果：在2项注意力测试中,剥夺组的成绩均低于安慰剂组和莫达非尼组,剥夺组第Ⅱ次的注意能力明显低于第Ⅰ次。安慰剂组和莫达非尼组在第Ⅰ次测试中无明显差异,第Ⅱ次测试中莫达非尼组的注意能力明显高于安慰剂组。结论：莫达非尼能明显改善睡眠剥夺后受损的注意力,受损程度越严重,莫达非尼的改善作用越显著。     

睡眠剥夺对大鼠大脑功能的影响

目的:探讨睡眠剥夺(SD)对大鼠大脑功能的影响。方法:采用小平台水环境法建立SD模型,以正常对照组和大平台对照组为对照,以学习记忆能力和脑电活动为指标,观察SD对大鼠脑功能的影响。结果:(1)大平台对照组学习记忆能力提高(P<0.05);SD组学习记忆能力降低(P<0.05、0.01);随着SD时间的延长,学习记忆能力下降越明显。(2)大平台对照组与正常对照组的脑电活动无差异(P>0.05);SD组与大平台组有差异(P<0.05、0.01),说明SD的确对大鼠的脑电活动有抑制作用,而且SD时间越长抑制越明显。结论:SD对大脑功能有明显的抑制作用。     

Effects of amphetamine and chlorpromazine on second-order escape behavior in squirrel monkeys

Three squirrel monkeys received extensive training under a concurrent free-operant avoidance, fixed-ratio escape schedule. The independent effects of D-amphetamine and chlorpromazine were assessed over a range of dose levels. The effects of D-amphetamine (0.03, 0.1, 0.3, and 1.0 mg/kg) on each monkey were dependent upon the subjects' control rates of responding. However, there was a clear rate-increasing effect on a relatively low rate of responding, and a rate-depressant effect on high response rates. Administration of chlorpromazine characteristically was followed by an overall depression of response rates. Dose combinations of 0.3 mg/kg chlorpromazine with D-amphetamine (0.1, 0.3, 1.0 mg/kg) illustrated the antagonistic effects of the two drugs. At the lowest amphetamine dosage, the chlorpromazine effect was unimpaired; at the 0.3 mg/kg dosage of each drug it was abolished. The rate-suppressive effect on high response rates of 1.0 mg/kg D-amphetamine was abolished when given together with 0.3 mg/ kg chlorpromazine. The present experiment demonstrates the phenomenon of amphetamine-chlorpromazine antagonism under conditions in which responding was maintained by the scheduled presentation of aversive stimulation.     

Effects of sleep deprivation on coronary heart disease

The presence of artificial light enables humans to be active 24 h a day. Many people across the globe live in a social culture that encourages staying up late to meet the demands of various activities, such as work and school. Sleep deprivation (SD) is a severe health problem in modern society. Meanwhile, as with cardiometabolic disease, there was an obvious tendency that coronary heart disease (CHD) to become a global epidemic chronic disease. Specifically, SD can significantly increase the morbidity and mortality of CHD. However, the underlying mechanisms responsible for the effects of SD on CHD are multilayered and complex. Inflammatory response, lipid metabolism, oxidative stress, and endothelial function all contribute to cardiovascular lesions. In this review, the effects of SD on CHD development are summarized, and SD-related pathogenesis of coronary artery lesions is discussed. In general, early assessment of SD played a vital role in preventing the harmful consequences of CHD.     

The effects of chlorpromazine and secobarbital on the reaction times of chronic schizophrenics

Summary Twelve male schizophrenics were given a simple visual reaction time test (RT) after single doses and chronic (11 days) administration of chlorpromazine and secobarbital. RT was tested under two conditions: irregular, in which preparatory intervals were presented randomly, and regular, in which the same preparatory intervals were given in consecutive order. Results under single doses indicated that secobarbital reduced intra-individual variability, while chlorpromazine did not significantly affect performance. Results under chronic administration indicated that neither drug had a significant effect on RT performance. These findings are different from those obtained by other investigators who have observed facilitation in schizophrenic psychomotor performance after chlorpromazine, and deficit in performance after barbiturates.This study is a revision of part of a dissertation submitted in partial fulfillment of the requirements for the degree Master of Arts, from the Catholic University of America, August 1957, by the senior author. Thanks are due Dr. John W, Stafford, who served as thesis advisor.This study was part of an N.I.M.H. research project run at St. Elizabeths Hospital, Washington, D.C., under the direction of the junior author, and reported elsewhere (Kornetsky, Pettit, Wynne, and Evarts 1959).This paper was presented in part at the 1958 meetings of the American Psychological Association.     

The nature of performance deficit under secobarbital and chlorpromazine in the monkey

The effects of secobarbital and chlorpromazine were studied in monkeys trained on a continuous, rapidly presented successive discrimination task. The subjects were implanted with epidural electrodes to monitor EEG during drug-induced impairment of performance. The analysis was focussed on the phase of drug effect during which both drugs induced intermittent lapses of responding.EEG and behavioral analysis of events following stimulus onset lead to the conclusion that the mechanism of error occurrence is different under the two drugs. The effect of secobarbital was prominent both in correct and incorrect trials; input, integration and output processes seemed to be functional but slowed down. This was inferred from the presence of EEG arousal, late or abortive motor responses (in the case of errors) and prolonged reaction time of correct responses. In contrast to this general, even effect, CPZ affected the performance in an all-or-none fashion. Periods of normal functioning (i.e., correct responses with moderately increased average reaction time) alternated with complete absence of responsiveness including the EEG arousal reaction. These findings support the view that secobarbital suppresses the behavior by affecting the level of wakefulness and thus impairing the functional condition of the whole central nervous system; chlorpromazine on the other hand exerts its effect by selectively blocking input processes subserving the EEG and behavioral arousal.Supported by Grant MH-12568 from the National Institute of Mental Health, Public Health Service.Research Scientist Awardee (5-K-5-MH-14, 915) of the National Institute of Mental Health.     

Effects of food deprivation on cocaine base smoking in rhesus monkeys

Studies have shown that both food deprivation and response cost have important influences on the magnitude of self-administration of a wide variety of psychoactive drugs. In an attempt to extend these findings to the smoked route of drug self-administration, the effects of food allotment and fixed-ratio (FR) value were evaluated in four male rhesus monkeys trained to smoke cocaine base. In the first phase of the experiment, monkeys were trained to self-administer smoked cocaine base under a chained progressive-ratio (PR), fixed-ratio (FR) schedule during daily experimental sessions. Monkeys were required to make 20 lever-press responses and then five inhalations on a smoking spout to obtain the first smoke delivery. The lever ratio then increased to 60, 140, 300, 620, 1260, 2540, and 4940 for each successive smoke delivery. The initial lever ratio value was reset to 20 at the beginning of each daily session. The body weights of three monkeys were determined under free-feeding conditions. Monkeys were then restricted to 100 g food and, when body weights had stabilized, the daily food allotment was increased to 150 g, approximately 210 g, or greater than 400 g (satiation). As the daily food allotment and body weight increased, the mean number of smoke deliveries decreased in two of three monkeys. In the second phase of the experiment, three monkeys were maintained under either food-satiated or food-restricted conditions. Body weights were maintained at approximately 90% of their free-feeding weights under food-restricted conditions. The cost of the drug (lever FR value) was constant within each experimental session, but was increased after 3 consecutive days of stable responding. Fixed-ratio values were increased from 128 to 256, 512, 1024, and 2048. Monkeys were required to complete the lever FR value and then to make five inhalations on the smoking spout to gain access to 1.0 mg/kg per delivery cocaine base. The mean number of smoke deliveries increased at FR 256, 512, and 1024 when monkeys were food-restricted as opposed to food-satiated. Correspondingly, the mean number of responses increased under food-restricted conditions. Responding continued to increase over a wider range of FR values, and the peak number of responses was higher under food-restricted, as opposed to food-satiated conditions. These results, using the smoking route of administration, are consistent with the hypothesis that food deprivation increases the self-administration of reinforcing drugs.     

Effects of flumazenil on recovery sleep and hormonal secretion after sleep deprivation in male controls

The effects of flumazenil, a benzodiazepine antagonist, on the sleep electroencephalogram (EEG) and neuroendocrine secretion in early morning recovery sleep (0500–0800 hours) following sleep deprivation (SD; 2300–0500 hours) were studied in seven healthy men. SD induced an increase in slow wave sleep (SWS), a decrease in sleep onset latency (SOL), an enhancement of EEG delta and theta power in non-rapid-eye-movement sleep, an increase in plasma human growth hormone (GH) concentration, and a decrease in plasma cortisol levels in recovery sleep (0500–0800 hours). Plasma GH, but neither plasma cortisol nor adrenocorticotrophic hormone (ACTH) concentration was attenuated during SD as compared to sleep (2300–0445 hours). The administration of flumazenil (3×1 mg intravenously) during recovery sleep resulted in an inhibition in SWS, an increase in stage 2 sleep, a selective reduction in delta and theta power, and a tendency to prolongation of SOL. Plasma GH concentration was decreased but plasma cortisol and ACTH remained unaffected. Since the SD-induced changes in sleep EEG and plasma GH secretion were antagonized by flumazenil, it is suggested that electrophysiological and hormonal effects of SD are mediated at least in part through GABAergic mechanisms.     

Amphetamine,scopolamine and chlorpromazine interactions on delayed matching performance in monkeys

Summary Two drug combinations, amphetamine-chlorpromazine and amphetamine-scopolamine, were examined in monkeys performing on a delayed matching test. Antagonism between the effects of amphetamine and chlorpromazine on both response rate and accuracy measures of performance was found. Amphetamine and scopolamine had antagonistic effects on response rate but synergistic effects on accuracy.Supported by Public Health Service Grant MH 01225. The authors wish to thank Mr. Bruce Levin for performing the computer analysis using the facilities of the Albert Einstein College of Medicine Computer Center. We also wish to thank Mrs. Toni Goldfarb, Mr. Jay Carley and Mr. Richard Pybus for indispensable technical assistance.     

Self-administration of the isomers of pentobarbital and secobarbital by rhesus monkeys

Previous studies have shown that the isomers of pentobarbital and secobarbital have behavioral effects that are qualitatively similar to those of the racemic mixture, but that the S-(-) isomers are more potent than the R-(+) isomers. The present study was designed to compare the reinforcing effects of the isomers of these compounds to those of the racemic mixtures in monkeys experienced in the intravenous self-administration of barbiturates. Rhesus monkeys (N = 3) were prepared with indwelling intravenous catheters and allowed to self-administer racemic pentobarbital in 1-hour sessions under a fixed ratio 5 schedule. When responding was stable, various doses of (+,-) pentobarbital, (+,-) secobarbital and single doses of both isomers of these compounds were substituted for the baseline drug in a mixed order. All of the compounds functioned as positive reinforcers in all monkeys. R-(+) isomer were self-administered at higher rates than the racemic mixtures which were self-administered at higher rates than the S-(-) isomers. The results demonstrate that both isomers of these barbiturates can function as positive reinforcers.     

Effects of chlordiazepoxide and secobarbital on film-induced anxiety

Summary Normal college students were given a single dose of chlordiazepoxide, secobarbital or placebo 85 min before being shown an anxiety-inducing film. Measures of sedation and of subjective anxiety were taken before and after the film. Results indicate that chlordiazepoxide and secobarbital had a measurable sedative action compared with placebo. Neither medication showed a significant anti-anxiety effect.This project was supported by NIMH grants MH-7753, MH-08954, a GRS grant to University Hospital, and by Roche Laboratories through Dr. Stanley Gould who also kindly supplied the chlordiazepoxide (Librium). The authors are pleased to acknowledge the assistance of Kim Atkinson, Susan Saaz, Betsy Janes, Andrew Strasfogel, George Fishman, and Mary Sheldon. Medical screening was done by Robert Rood, M.D. Films were borrowed from Audio-Visual Support Center, Mr. R. A. Cudworth, Director, First Army Base, Boston, and from the Boston Public Library.     

Enzyme activity in sleep and sleep deprivation

Liver tyrosine transaminase activity is low during the day when the rats are mostly asleep and high during the night when they are awake. When wakefulness was imposed for 8 hr during daylight on the day of the experiment and the rats were allowed to sleep for the following 3 hr during darkness, the tyrosine transaminase activity became high during the day and low at night. That this reversal in enzyme activity is not mediated by the pituitary-adrenal axis is demonstrated by the fact that in adrenalectomized rats tyrosine transaminase activity increased during the day in the sleep deprived rats. However, in these rats the enzyme activity did not become low in the sleep-deprived-sleeping condition. Changes in tryptophan pyrrolase activity during sleep deprivation were demonstrated to be mediated by the pituitary-adrenal axis.     

Effects of modafinil on cognitive performance and alertness during sleep deprivation

The performance- and alertness-sustaining/restoring effects of modafinil during sleep deprivation in normal, healthy adults were reviewed. Results indicate that modafinil is efficacious for sustaining/restoring objective performance and alertness during sleep deprivation with few adverse effects. At appropriate dosages, modafinil restores performance and alertness to non-sleep deprived levels. Modafinil also impairs post-sleep deprivation recovery sleep, but from the few studies available addressing this issue, it is unclear whether these sleep impairments translate into post-sleep performance impairments. Further research is needed to determine whether modafinil restores performance on simple cognitive tasks only or whether modafinil additionally restores executive functions (e.g., abstract thought, critical reasoning, planning, decision-making, situational awareness, and effective judgment) which are critical in most modern operational settings. In addition, studies are needed to determine whether modafinil use during sleep deprivation is preferable to that of other available controlled stimulants (such as dextroamphetamine) or non-controlled stimulants (such as caffeine). Such studies would be comprised of direct, head-to-head comparisons among various stimulants across a range of dosages.